The immune system recognizes and distinguishes substances as self versus nonself, and defends the body against nonself substances. The importance of this distinction is evident in a variety of conditions such as autoimmune diseases, rejection of transplanted tissues or organs, allergic reactions, cancer and infectious diseases, and modes of treatments such as immunotherapy and gene therapy. For example, in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and myasthenia gravis, the body mistakenly treats self as nonself and thus destroys its own components. In transplant rejection, immunosuppressive drugs are administered to a recipient to prevent the recipient's immune system from rejecting a true nonself substance so that the recipient can accept the transplanted tissue or organ as its own. In allergic reactions such as asthma, eczema and hay fever, there is an immune hypersensitivity in some individuals that occurs immediately following contact with an antigen. In infectious diseases a microbe such as a bacterium, parasite or virus stimulates an immune response. The microbe or a microbe subunit may be formulated as a vaccine to provide prophylactic protection against subsequent infection. In cancer, unlike the other conditions, an immune response is not mounted and the lack of an immune response plays a role in the uncontrolled growth of malignant cells. A wide variety of foreign substances, termed antigens or immunogens, elicit an immune response and thus are targeted by the immune system. Examples of antigens include, but are not limited to, infectious disease agents such as bacteria, viruses, parasites and fungi as well as mites, pollen, animal dander, drugs, toxins and chemicals.
The immune system is a complex network of cells, tissues and organs that directly and indirectly target and ultimately destroy foreign substances. Of the various cells involved in mounting an immune response, lymphocytes are one type of white blood cells that have a crucial role. One type of lymphocyte is the B lymphocyte (B cell) that targets and indirectly destroys foreign substances by mounting a humoral immune response to produce antibodies against specific antigens. The other type of lymphocyte is the T lymphocyte (T cell) that targets and directly kills foreign substances by mounting a cell-mediated immune response. There are three major subtypes of T cells designated as T helper cells, T suppressor cells, and T cytotoxic cells. T helper cells are of two types: T.sub.H 1 and T.sup.H 2 cells. T.sup.H 2 cells help B cells mount a humoral immune response and help T cytotoxic cells maintain themselves by producing growth factors needed by the T cytotoxic cells. T.sup.H 2 cells express the CD4 glycoprotein antigen. T suppressor cells inhibit or suppress T helper cells; they express the CD8 glycoprotein antigen. T cytotoxic cells, also called cytotoxic T lymphocytes (CTL), express the CD8 glycoprotein antigen and are a subset of T cells that kill cells expressing a specific antigen upon direct contact with these target cells. Pre-CTL are T cells that are committed to the CTL lineage, have undergone thymic maturation and are already specific for a particular antigen, but lack cytolytic function. CTL are important effector cells in three settings: (1) intracellular infections of non-phagocytic cells or infections that are not completely contained by phagocytosis such as viral infections, (2) infections by bacteria such as Listeria monocytogenes, and (3) acute allograft rejection and rejection of tumors.
An immunogenic response is most predictably induced by using a protein as the immunogen. In immunotherapy, the protein is frequently administered parenterally, for example by injection. While injections are inconvenient and uncomfortable to many patients, they have heretofore been a common route of administration because orally administered protein is degraded by protease enzymes and acid in the stomach and enzymes in the small intestines. It has been demonstrated that oral administration of a soluble protein such as the model antigen ovalbumin (OVA) results in the induction of immune tolerance, characterized by the loss of either antibody or T cell response to the protein antigen. However, U.S. Pat. No. 5,591,433 discloses that immunologically active biomolecules and other therapeutic proteins can be orally administered by microencapsulating the protein and coating the microsphere to form a pH-sensitive enterocoated microsphere particle that is resistant to the action of digestive proteolytic enzymes and acids. The microspheres disclosed in the '433 patent consist of protein bound to an inert particle having a mesh size of about 30-35 mesh (about 600 .mu.m to about 500 .mu.m) diameter and coated with an acid stable polymer. What is needed, however, is a method of better selecting and selectively modulating a particular immune response from the complex immune repertoire to better respond to different antigenic stimuli in different conditions requiring treatment.
For example, current cancer treatments include combinations of chemotherapy, radiation therapy, and surgical excision of some or all of a solid tumor. Each of these treatment mechanisms is targeted to eliminating malignant cells but is performed at the expense of destroying nonmalignant cells. Thus, none of these treatments utilize the body's own capacity for cell destruction, namely, the immune system and particularly the cytotoxic T cells, to kill malignant cells. A method of increasing an immune response and/or selectively stimulating the cytotoxic T cell population would therefore be a valuable supplement to traditional treatment methods. In addition, such a method would operate without the adverse effects of chemotherapeutic drugs, radiation, or surgical insult. Cancer cells, however, are not recognized as foreign by the immune system and thus are not targeted for destruction. One goal in developing cancer treatments is to stimulate the immune system to mount an immune response against cancer cells. Of the three major T cell types, the T cytotoxic cells frequently directly target and destroy cancer cells. Thus, selectively increasing the T cytotoxic cell subtype may be an advantageous way to check the unregulated cell division that is a hallmark of cancer cells.
As another example, the T cytotoxic cells also directly target and destroy extracellular infectious disease agents and infectious disease agents in infected cells. Cell mediated immunity consists of two types of reactions. The first type is macrophage activation resulting in the killing of phagocytized microbes. The second type is lysis of infected cells by CD8+ cytotoxic T lymphocytes (CTL). Differences among individuals in the patterns of immune responses to intracellular microbes, for example in HIV infection, are important determinants of disease progression and clinical outcome. The selective increase in the T cytotoxic cell subtype may be used to combat infectious diseases.
There is thus a need for a method and composition to better modulate and/or selectively stimulate an immune response. Such a method and composition would find wide use in immunotherapy or gene therapy for conditions such as allergies, infectious diseases, cancer, transplant rejection, and autoimmune diseases. Such a method and composition would also be a valuable prophylactic and/or therapeutic supplement to current methods of treating these conditions.